The introduction of antiretroviral therapy (ART) has improved survival among people with HIV infection (HIV+), but this success is accompanied by a high burden of cardiometabolic diseases, including diabetes mellitus. Studies of HIV-negative persons demonstrate reproducible relationships between monocyte and T- cell subsets, glucose intolerance, and diabetes, but the lack of similar data from persons with HIV infection, a disease characterized by alterations in innate and adaptive immune function, represents a major research gap. Studies to date of immune function and glucose tolerance in HIV+ persons generally 1) used non- specific soluble inflammatory biomarkers and did not investigate immune cells of the innate (e.g., monocytes) and adaptive systems (e.g., T-cells); 2) did not included HIV-negative controls, and therefore could not assess whether HIV status affects diabetes risk independent of immune and other clinical risk factors; and 3) did not assess how immune cell subsets, activation, and/or senescence interact with non-immune risk factors, such as visceral and hepatic fat, to affect insulin resistance and beta-cell dysfunction. Our proposal addresses these research gaps. Our overarching hypothesis is that persistent monocyte activation and a confluence of T-cell changes, including a lower proportion of regulatory T-cells and higher Type 1 T-helper (TH1) cells, are central to the development of HIV-associated diabetes. Aim 1 will be the first study to examine if differences in the phenotype and function of immune cell subsets can explain differences in incident diabetes cases in HIV+ versus HIV-negative people, which will be possible by exploiting the unique resources of the Veterans Aging Cohort Study biomarker cohort (VACS BC). The VACS BC is a prospective cohort of 2,378 (65% HIV+) adults with soluble biomarkers, monocyte and T-cell subsets; longitudinal health and behavior survey data, and access to all clinical, laboratory, and medication data in the integrated VA health system. These data allow for the comprehensive identification of incident diabetes in HIV+ and HIV- negative subjects (222 incident diagnoses to date) in the context of immunologic and clinical risk factors. Aim 2 will determine how the profound changes in immune cell activation, exhaustion, and subsets that are characteristic of HIV infection impact insulin resistance and insulin secretion. We will assess how temporal changes in monocyte and T-cell phenotype and function are related to changes in glucose tolerance among 120 HIV+ adults recently started on ART at Vanderbilt University. Our approach will incorporate intravenous and oral glucose tolerance assessments, monocyte and T-cell flow cytometry, health and behavior assessments, and CT measurements of visceral, hepatic, and other adipose tissue deposits. Our study is designed to define the pro-diabetic immunologic phenotype in HIV+ persons on ART. Our findings could lead to the integration of markers relevant to metabolic disease into routine-care flow cytometry, and identify patients with high-risk immunologic profiles for future mechanistic studies and therapeutic trials.